Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Thomas Powles, Piotr Tomczak, Se Hoon Park, Balaji Venugopal, Thomas Ferguson, Stefan N Symeonides, Jaroslav Hajek, Howard Gurney, Yen-Hwa Chang, Jae Lyun Lee, Naveed Sarwar, Antoine Thiery-Vuillemin, Marine Gross-Goupil, Mauricio Mahave, Naomi B Haas, Piotr Sawrycki, Joseph E Burgents, Lei Xu, Kentaro Imai, David I Quinn, Toni K Choueiri, Piotr Tomczak, Toni Choueiri, Se Hoon Park, Balaji Venugopal, Thomas R. Ferguson, Jaroslav Hajek, Tzu-Ping Lin, Stefan N. Symeonides, Jae Lyun Lee, Piotr Sawrycki, Naomi B. Haas, Howard P. Gurney, Mauricio Mahave, Naveed Sarwar, Antoine Thiery-Vuillemin, Marine Gross-Goupil, Christine Chevreau, John M. Burke, Gurjyot Doshi, Bohuslav Melichar, Delphine Topart, Stephane Oudard, Evgeniy Kopyltsov, Hans-Joerg Hammers, David I. Quinn, Ajjai Alva, Juliana de Janoski Menezes, Adriano Goncalves e Silva, Eric W. Winquist, Alketa Hamzaj, Giuseppe Procopio, Boguslawa Karaszewska, Ewa M. Nowakowska-Zajdel, Boris Y. Alekseev, Rustem A. Gafanov, Adel Izmailov, Andrey Semenov, Sergey G. Afanasyev, Oleg N. Lipatov, Thomas B. Powles, Sandy Srinivas, David McDermott, Samith T. Kochuparambil, Ian D. Davis, Katriina Peltola, Roberto Sabbatini, Jinsoo Chung, Michail I. Shkolnik, Vsevolod B. Matveev, Pablo Gajate Borau, Steven McCune, Thomas E. Hutson, Alejandro Dri, Silvio Correia Sales, Carrie Yeung, Carmen Marcela Alcala Castro, Peter Bostrom, Brigitte Laguerre, Consuelo Buttigliero, Ugo de Giorgi, Eugeniy A. Fomin, Yousef Zakharia, Clara Hwang, Eric A. Singer, Jeffrey T. Yorio, David Waterhouse, Ruben Dario Kowalyszyn, Margarita Sonia Alfie, Eduardo Yanez Ruiz, Tomas Buchler, Krista Kankaanranta, Gianluigi Ferretti, Go Kimura, Kazuo Nishimura, Naoya Masumori, Satoshi Tamada, Haruaki Kato, Hiroshi Kitamura, Iwona Danielewicz, Joanna Wojcik-Tomaszewska, Nuria Sala Gonzalez, Kun-Yuan Chiu, Michael B. Atkins, Elisabeth Heath, Gustavo Adolfo Rojas-Uribe, Manuel Enrique Gonzalez Fernandez, Susan Feyerabend, Sandro Pignata, Kazuyuki Numakura, Bozena Cybulska Stopa, Ruslan Zukov, Miguel Angel Climent Duran, Pablo Jose Maroto Rey, Alvaro Montesa Pino, Chao-Hsiang Chang, Salil Vengalil, Tom S. Waddell, Patrick W. Cobb, Ralph Hauke, Daniel M. Anderson, John Sarantopoulos, Theodore Gourdin, Tian Zhang, Gautam Jayram, Luis Enrique Fein, Carole Harris, Patricia Medeiros Milhomem Beato, Francisco Flores, Angela Estay, Juan Andres Rubiano, Jens Bedke, Stefan Hauser, Andreas Neisius, Jonas Busch, Satoshi Anai, Hiroyuki Tsunemori, Dariusz Sawka, Bozena Sikora-Kupis, Jose Angel Arranz, Ignacio Delgado, Chung-Hsin Chen, Elizabeth Gunderson, Scott Tykodi, Alan Koletsky, Kevin Chen, Manish Agrawal, Diego Lucas Kaen, Juan Pablo Sade, Marcelo Daniel Tatangelo, Francis Parnis, Fernando Maciel Barbosa, Genevieve Faucher, Nayyer Iqbal, Daniele Marceau, Jean-Benoit Paradis, Nawar Hanna, Alejandro Acevedo, Carolina Ibanez, Luis Villanueva, Pedro Pablo Galaz, Isabel Cristina Durango, Ray Manneh, Zdenek - Kral, Petra Holeckova, Heikki Hakkarainen, Hanna Ronkainen, Sophie Abadie-Lacourtoisie, Sophie Tartas, Peter J. Goebell, Marc-Oliver Grimm, Thomas Hoefner, Manfred Wirth, Andrej Panic, Wolfgang Schultze-Seemann, Akira Yokomizo, Ryuichi Mizuno, Hirotsugu Uemura, Masatoshi Eto, Masao Tsujihata, Yoshihisa Matsukawa, Yoji Murakami, Miso Kim, Paul Hamberg, Malgorzata Marczewska-Skrodzka, Cezary Szczylik, Alison C. Humphreys, Peter Jiang, Birendra Kumar, Gary Lu, Arpita Desai, Jose Antonio Karam, George Keogh, Mark Fleming, Juan Jose Zarba, Viviana E. Leiva, Guillermo Ariel Mendez, Samuel J. Harris, Stephen J. Brown, Joao Neif Antonio Junior, Rita de Cassia Costamilan, Roberto Odebrecht Rocha, David Muniz, Leandro Brust, Aly-Khan Lalani, Jeffrey Graham, Michael Levesque, Francisco Orlandi, Rostislav Kotasek, Jean L. Deville, Delphine Borchiellini, Axel Merseburger, Michael Rink, Frederik Roos, Ray McDermott, Masafumi Oyama, Yoshiaki Yamamoto, Yoshihiko Tomita, Yuji Miura, Naomasa Ioritani, Hans Westgeest, Tomasz Kubiatowski, Wieslaw Bal, Regina Girones Sarrio, Julie Rowe, Debra M. Prow, Francis Senecal, Neda Hashemi-Sadraei, Scott W. Cole, Stephan D. Kendall, Donald A. Richards, Ian D. Schnadig, Mukul Gupta
Journal: The Lancet Oncology (2022)

The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints.In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334.Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7-36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50-0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3-4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab.Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy.Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.